- Synthesis, biological evaluation, and structure-activity relationships of new tubulin polymerization inhibitors based on 5-amino-1,2,4-triazole scaffold
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Based on our previous research, thirty new 5-amino-1H-1,2,4-triazoles possessing 3,4,5-trimethoxyphenyl moiety were synthesized, and evaluated for antiproliferative activities. Among them, compounds IIa, IIIh, and IIIm demonstrated significant antiproliferative activities against a panel of tumor cell lines, and the promising compound IIIm dose-dependently caused G2/M phase arrest in HeLa cells. Furthermore, analogue IIa exhibited the most potent tubulin polymerization inhibitory activity with an IC50 value of 9.4 μM, and molecular modeling studies revealed that IIa formed stable interactions in the colchicine-binding site of tubulin, suggesting that 5-amino-1H-1,2,4-triazole scaffold has potential for further investigation to develop novel tubulin polymerization inhibitors with anticancer activity.
- Yang, Fang,Chen, Lin,Lai, Jin-Mei,Jian, Xie-Er,Lv, Dong-Xin,Yuan, Li-Li,Liu, Yu-Xia,Liang, Feng-Ting,Zheng, Xiao-Lan,Li, Xiong-Li,Wei, Li-Yuan,You, Wen-Wei,Zhao, Pei-Liang
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- Synthesis and Biological Evaluation of Dithiobisacetamides as Novel Urease Inhibitors
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Thirty-eight disulfides containing N-arylacetamide were designed and synthesized in an effort to develop novel urease inhibitors. Biological evaluation revealed that some of the synthetic compounds exhibited strong inhibitory potency against both cell-free urease and urease in intact cell with low cytotoxicity to mammalian cells even at concentration up to 250 μM. Of note, 2,2′-dithiobis(N-(2-fluorophenyl)acetamide) (d7), 2,2′-dithiobis(N-(3,5-difluorophenyl)acetamide) (d24), and 2,2′-dithiobis(N-(3-fluorophenyl)acetamide) (d8) were here identified as the most active inhibitors with IC50 of 0.074, 0.44, and 0.81 μM, showing 32- to 355-fold higher potency than the positive control acetohydroxamic acid. These disulfides were confirmed to bind urease without covalent modification of the cysteine residue and to inhibit urease reversibly with a mixed inhibition mechanism. They also showed very good anti-Helicobacter pylori activities with d8 showing a comparable potency to the clinical used drug amoxicillin. The impressive in vitro biological profile indicated their immense potential as therapeutic agents to tackle H. pylori caused infections.
- Fang, Hai-Lian,Li, Su-Ya,Li, Wei-Yi,Liu, Mei-Ling,Ouyang, Hui,Song, Wan-Qing,Xiao, Zhu-Ping,Ye, Ya-Xi,Zhu, Hai-Liang
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- Discovery of new indole-based 1,2,4-triazole derivatives as potent tubulin polymerization inhibitors with anticancer activity
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Thirty-six novel indole-based 1,2,4-triazole derivatives were designed and synthesized through the molecular hybrid strategy. The bioassay results revealed that 9p displayed excellent antiproliferative efficacies in the nanomolar range against HeLa cells. Importantly, the compound exhibited no obvious cytotoxic activity (IC50 > 100 μM) toward HEK-293, a normal human embryonic kidney cell line. Mechanism analysis indicated that 9p significantly arrested the cell cycle at the G2/M phase and induced apoptosis in HeLa cells in a dose-dependent manner. Further evidence demonstrated that the promising compound effectively inhibited tubulin polymerization with an IC50 value of 8.3 μM, and molecular docking studies revealed that 9p well occupied the colchicine-site in tubulin. The present study highlights that indole-triazole hybrids might be used as a promising scaffold to develop novel tubulin polymerization inhibitors for cancer treatment.
- Chen, Lin,Jian, Xie-Er,Liu, Yu-Xia,Ma, Yu-Feng,Yang, Fang,You, Wen-Wei,Zhao, Pei-Liang
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p. 21869 - 21880
(2021/12/09)
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- Discovery and optimization of 3,4,5-trimethoxyphenyl substituted triazolylthioacetamides as potent tubulin polymerization inhibitors
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Based on our previous research, three series of new triazolylthioacetamides possessing 3,4,5-trimethoxyphenyl moiety were synthesized, and evaluated for antiproliferative activities and inhibition of tubulin polymerization. The most promising compounds 8b and 8j demonstrated more significant antiproliferative activities against MCF-7, HeLa, and HT-29 cell lines than our lead compound 6. Moreover, analogues 8f, 8j, and 8o manifested more potent antiproliferative activities against HeLa cell line with IC50 values of 0.04, 0.05 and 0.16 μM, respectively, representing 100-, 82-, and 25-fold improvements of the activity compared to compound 6. Furthermore, the representative compound, 8j, was found to induce significant cell cycle arrest at the G2/M phase in HeLa cell lines via a concentration-dependent manner. Meanwhile, compound 8b exhibited the most potent tubulin polymerization inhibitory activity with an IC50 value of 5.9 μM, which was almost as active as that of CA-4 (IC50 = 4.2 μM). Additionally, molecular docking analysis suggested that 8b formed stable interactions in the colchicine-binding site of tubulin.
- Yang, Fang,He, Cai-Ping,Diao, Peng-Cheng,Hong, Kwon Ho,Rao, Jin-Jun,Zhao, Pei-Liang
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- Small-Molecule Choline Kinase Inhibitors as Anti-Cancer Therapeutics
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Small molecule choline kinase inhibitors having the following formula: are provided herein. Also provided herein are pharmaceutical compositions containing Formula I compounds, together with methods of treating cancer, methods of inhibiting choline kinase enzymatic activity, and methods of treating tumors by administering an effective amount of a Formula I compound.
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Page/Page column 12; 27-28
(2011/10/31)
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